Amino Acid Changes Research Articles

Plasmodium falciparum CyRPA glycan binding does not explain adaptation to humans.

The human malaria parasite Plasmodium falciparum evolved from a parasite that infects gorillas, termed Plasmodium praefalciparum. The sialic acids on glycans on the surface of erythrocytes differ between humans and other apes. It has recently been shown that the P. falciparum cysteine-rich protective antigen (PfCyRPA) binds human sialoglycans as an essential step in the erythrocyte invasion pathway, while that of the chimpanzee parasite Plasmodium reichenowi has affinities matching ape glycans. Two amino acid changes, at sites 154 and 209, were shown to be sufficient to switch glycan binding preferences and inferred to reflect adaptation of P. falciparum to humans. However, we show that sites 154 and 209 are identical in P. falciparum and P. praefalciparum, with no other differences located in or near the CyRPA glycan binding sites. Thus, the gorilla precursor appears to have already been preadapted to bind human sialoglycans.

Convergent evolution and predictability of gene copy numbers associated with diets in mammals.

Convergent evolution, the evolution of the same or similar phenotypes in phylogenetically independent lineages, is a widespread phenomenon in nature. If the genetic basis for convergent evolution is predictable to some extent, it may be possible to infer organismic phenotypes and the capability of organisms to utilize new ecological resources based on genome sequence data. While repeated amino acid changes have been studied in association with convergent evolution, relatively little is known about the potential contribution of repeated gene copy number changes. In this study, we explore whether gene copy number changes of particular gene families are linked to diet shifts in mammals and assess if trophic ecology can be inferred from the copy numbers of a specific set of gene families. Using 86 mammalian genome sequences, we identified 24 gene families with a trend toward higher copy numbers in herbivores, carnivores, and omnivores, even after phylogenetic corrections. We were able to confirm previous findings on genes such as amylase, olfactory receptors, and xenobiotic metabolism genes, and identify novel gene families whose copy numbers correlate with dietary patterns. For example, omnivores exhibited higher copy numbers of genes encoding regulators of translation. We also established a discriminant function based on the copy numbers of 13 gene families that can help predict trophic ecology to some extent. These findings highlight a possible association between convergent evolution and repeated copy number changes in specific gene families, suggesting the potential to develop a method for predicting animal ecology from genome sequence data.

Three cases of hemoglobin M disease in a family lineage: Case report and literature review.

This study presents a case of hemoglobin M disease (HMD), a rare inherited disorder characterized by persistent cyanosis and hypoxemia, observed across 3 generations within a single family. The diagnosis of HMD poses significant challenges, particularly in asymptomatic individuals, due to its rarity and the subtlety of its symptoms. Notably, there is a scarcity of reports on methemoglobinemia in pediatric populations, which further complicates early detection and intervention. The primary objectives of this study are to enhance awareness of HMD, to advocate for accurate diagnosis and timely treatment, and to underscore the necessity of considering this condition in patients with a familial history of cyanosis. A 6-year-old boy presented to our hospital with fatigue and cyanosis in his lips and mouth. Both the child's mother and grandfather had a history of similar symptoms since their childhood. Diagnosis of hemoglobin M disease. The patient was treated with vitamin C. Genetic testing revealed that the patient and her mother carried the c.190C > T mutation, leading to the p.H63Y amino acid change linked to the methemoglobin (MetHb) mutation. Despite undergoing vitamin C therapy, the patient's symptoms of cyanosis and fatigue persisted. Hemoglobin M disease can be readily diagnosed with a delay. Methemoglobinemia should be considered in patients with a family history of cyanosis but no cardiopulmonary disease. Hospital blood gas analysis should include a protocol for detecting methemoglobin, and genetic testing can help confirm the diagnosis.

ZW sex chromosome differentiation in paleognathous birds is associated with mitochondrial effective population size but not mitochondrial genome size or mutation rate.

Eukaryotic genome size varies considerably, even among closely related species. The causes of this variation are unclear, but weak selection against supposedly costly "extra" genomic sequences has been central to the debate for over 50 years. The mutational hazard hypothesis, which focuses on the increased mutation rate to null alleles in superfluous sequences, is particularly influential, though challenging to test. This study examines the sex chromosomes and mitochondrial genomes of 15 flightless or semi-flighted paleognathous bird species. In this clade, the non-recombining portion of the W chromosome has independently expanded stepwise in multiple lineages. Given the shared maternal inheritance of the W chromosome and mitochondria, theory predicts that mitochondrial effective population size (Ne) should decrease due to increased Hill-Robertson Interference in lineages with expanded non-recombining W regions. Our findings support the extent of the non-recombining W region with three indicators of reduced selective efficiency: (1) the ratio of non-synonymous to synonymous nucleotide changes in the mitochondrion, (2) the probability of radical amino acid changes, and (3) the number of ancient, W-linked genes lost through evolution. Next, we tested whether reduced Ne affects mitochondrial genome size, as predicted by weak selection against genome expansion. We find no support for a relationship between mitochondrial genome size and expanded non-recombining W regions, nor with increased mitochondrial mutation rates (predicted to modulate selective costs). These results highlight the utility of non-recombining regions and mitochondrial genomes for studying genome evolution and challenge the general idea of a negative relation between the efficacy of selection and genome size.

Cold climate-driven convergent evolution among angiosperms.

Convergent and parallel evolution occur more frequently than previously thought. Here, we focus on the evolutionary adaptations of angiosperms to sub-zero temperatures. We begin by introducing the research history of convergent and parallel evolution, defining all independent similarities as convergent evolution. Our analysis reveals that frost zones (periodic or constant), covering 49.1% of Earth's land surface, host 137 angiosperm families with over 90% of their species thriving in these regions. On this context, we revisit the global biogeography and evolutionary trajectories of plant traits, such as herbaceous form and leaf deciduousness, which are likely evasion strategies for frost adaptation. At the physiological and molecular levels, many angiosperms have independently evolved cold-acclimation mechanisms through multiple pathways beyond the well-characterized CBF/DREB1 regulatory pathway. The convergent adaptations occur across various molecular levels, including amino acid substitutions and changes in gene duplication and expression within the same or similar functional pathways; however, identical amino acid changes are rare. Moreover, we highlight the prevalence of polyploidy in frost zones and occurrence of paleopolyploidization events during global cooling. These patterns suggest repeated evolution in cold climates. Finally, we discuss plant domestication, predict climate zone shifts due to global warming, and their effects on plant migration and in-situ adaptation. Overall, integrating ecological and molecular perspectives is essential for understanding and forecasting plant responses to climate change.

Typing Arctic and Africa-2 clades of rabies virus using clade-defining single nucleotide polymorphisms.

Rabies is a deadly neurotropic, zoonotic disease with a mortality rate of 100% after symptoms appear. Rabies virus (RABV) is the primary cause of rabies disease in humans, and it mainly spreads via dog bites in developing countries. Over the course of RABV evolution, multiple RABV variants, called clades, have emerged. However, our understanding of these clades is limited, as the only method to identify a clade is sequencing, followed by phylogeny. In this study, we have developed a rapid, PCR-based method for typing two RABV clades. We utilised highly conserved amino acid changes specific to the Arctic and Africa-2 clades of the rabies virus (RABV). A single nucleotide substitution from adenine to thymine at position 178 within the nucleoprotein gene was found to be clade-specific in the Arctic clade. Similarly, adenine at position 638 is a distinctive marker for the Africa-2 clade. The assay demonstrated high specificity and offers the added benefit of PCR-based amplification, enabling virus detection even when viral titers are low. The assay can identify the Arctic clade and Africa-2 clade without sequencing and is highly specific and sensitive. Furthermore, this method can be adapted to detect other RABV clades and a wide range of viruses.

Isolation and characterization of haploid heterothallic beer yeasts

Improving ale or lager yeasts by conventional breeding is a non-trivial task. Domestication of lager yeasts, which are hybrids between Saccharomyces cerevisiae and Saccharomyces eubayanus, has led to evolved strains with severely reduced or abolished sexual reproduction capabilities, due to, e.g. postzygotic barriers. On the other hand, S. cerevisiae ale yeasts, particularly Kveik ale yeast strains, were shown to produce abundant viable spores (~ 60%; Dippel et al. Microorganisms 10(10):1922, 2022). This led us to investigate the usefulness of Kveik yeasts for conventional yeast breeding. Surprisingly, we could isolate heterothallic colonies from germinated spores of different Kveik strains. These strains presented stable mating types in confrontation assays with pheromone-sensitive tester strains. Heterothallism was due to inactivating mutations in their HO genes. These led to amino acid exchanges in the Ho protein, revealing a known G223D mutation and also a novel G217R mutation, both of which abolished mating type switching. We generated stable MATa or MATα lines of four different Kveik yeasts, named Odin, Thor, Freya and Vör. Analyses of bud scar positions in these strains revealed both axial and bipolar budding patterns. However, the ability of Freya and Vör to form viable meiotic offspring with haploid tester strains demonstrated that these strains are haploid. Fermentation analyses indicated that all four yeast strains were able to ferment maltose and maltotriose. Odin was found to share not only mutations in the HO gene, but also inactivating mutations in the PAD1 and FDC1 genes with lager yeasts, which makes this strain POF-, i.e. not able to generate phenolic off-flavours, a key feature of lager yeasts. These haploid ale yeast-derived strains may open novel avenues also for generating novel lager yeast strains by breeding or mutation and selection utilizing the power of yeast genetics, thus lifting a block that domestication of lager yeasts has brought about.Key points• Haploid Kveik ale yeasts with stable MATa and MATα mating types were isolated.• Heterothallic strains bear mutant HO alleles leading to a novel inactivating G217R amino acid change.• One strain was found to be POF- due to inactivating mutations in the PAD1 and FDC1 gene rendering it negative for phenolic off-flavor production.• These strains are highly accessible for beer yeast improvements by conventional breeding, employing yeast genetics and mutation and selection regimes.

Inference of the demographic histories and selective effects of human gut commensal microbiota over the course of human history.

Despite the importance of gut commensal microbiota to human health, there is little knowledge about their evolutionary histories, including their demographic histories and distributions of fitness effects (DFE) of mutations. Here, we infer the demographic histories and DFEs for amino-acid changing mutations of 39 of the most prevalent and abundant commensal gut microbial species found in Westernized individuals over timescales exceeding human generations. Some species display contractions in population size and others expansions, with several of these events coinciding with several key historical moments in human history. DFEs across species vary from highly to mildly deleterious, with differences between accessory and core gene DFEs largely driven by genetic drift. Within genera, DFEs tend to be more congruent, reflective of underlying phylogenetic relationships. Together, these findings suggest that gut microbes have distinct demographic and selective histories.

Ganciclovir Resistance-Linked Mutations in the HCMV UL97 Gene: Sanger Sequencing Analysis in Samples from Transplant Recipients at a Tertiary Hospital in Southern Brazil.

Background/Objectives: Human cytomegalovirus (HCMV) DNAemia remains a significant concern for transplant recipients, largely due to mutations in the viral genome that may lead to antiviral-resistant strains. Mutations in the UL97 gene are frequently associated with resistance to ganciclovir (GCV), highlighting the importance of early mutation detection to effectively manage viremia. This study aimed to optimize a Sanger sequencing protocol for analyzing GCV resistance-linked mutations in the HCMV UL97 gene from plasma samples of transplant patients treated at Hospital de Clínicas de Porto Alegre, Rio Grande do Sul, Brazil. Methods: A nested-PCR approach combined with a touchdown PCR method was employed to enhance the sensitivity and specificity of the sequencing analysis. Results: The study sample included various transplants, encompassing solid organ and bone marrow recipients. Among 16 sequenced samples, 8 exhibited nucleotide substitutions resulting in amino acid changes. Notably, the A594V and C603W mutations, associated with GCV resistance, were identified in four samples. Additionally, three mutations with unknown phenotypic impact (P509L, A628T, and H662Y) and two viral polymorphisms (N510S and D605E) were detected. Furthermore, double peaks in the Sanger electropherograms, indicative of mixed viral populations of HCMV were observed in seven samples. Conclusions: The optimized Sanger sequencing protocol provides a cost-effective solution for detecting GCV resistance mutations in HCMV UL97 among transplant recipients. This approach could improve the understanding of HCMV strain dynamics and serve as a valuable tool for long-term patient monitoring, particularly within resource-constrained settings such as the public health systems of middle-income countries.

Testing the kinetic tradeoff between bicarbonate versus phosphoenolpyruvate affinity and glucose-6 phosphate response of phosphoenolpyruvate carboxylase from two C4grasses.

Phosphoenolpyruvate (PEP) carboxylase (PEPC) has an anaplerotic role in central plant metabolism but also initiates the carbon concentrating mechanism during C4 photosynthesis. The C4 PEPC has different binding affinities (Km) for PEP (K0.5PEP) and HCO3- (K0.5HCO3), and allosteric regulation by glucose-6-phosphate (G6-P) compared to non-photosynthetic isoforms. These differences are linked to specific changes in amino acids within PEPC. For example, region II (residues 302-433, Zea mays numbering) has been identified as important for G6-P regulation and within this region residue 353 may be conserved in C4 PEPC enzymes. Additionally, residue 780 influences the C4 PEPC kinetic properties and may interact with region II as well as residue 353 to influence G6-P regulation. We test the hypothesis that variation within region II, including residue 353, and their interactions with residue 780 influence the kinetic and allosteric regulation by G6-P of two C4 PEPC isozymes from two C4 grasses. The data does not support a kinetic tradeoff between K0.5HCO3 and K0.5PEP in these PEPC isozymes. Additionally, these enzymes had different response to G6-P that was only partially attributed to region II, residue 353 and residue 780. This data provides new insights into factors influencing the kinetic variation of C4 PEPC isozymes.

Comparative organelle genomics in Daphniphyllaceae reveal phylogenetic position and organelle structure evolution

The family Daphniphyllaceae has a single genus, and no relevant comparative phylogenetic study has been reported on it. To explore the phylogenetic relationships and organelle evolution mechanisms of Daphniphyllaceae species, we sequenced and assembled the chloroplast and mitochondrial genomes of Daphniphyllum macropodum. We also conducted comparative analyses of organelles in Daphniphyllaceae species in terms of genome structure, phylogenetic relationships, divergence times, RNA editing events, and evolutionary rates, etc. Results indicated differences in the evolutionary patterns of the plastome and mitogenome in D. macropodum. The plastome had a more conserved structure but a faster nucleotide substitution rate, and the mitogenome showed a more complex structure while the mitotic genome shows a more complex structure but a slower nucleotide substitution rate. We identified several unidirectional protein-coding gene transfer events from the plastome to the mitogenome based on homology analysis, but no transfer events occurred from the mitogenome to the plastome. Multiple TE fragments existed in organelle genomes, and two organelles showed different preferences for nuclear TE insertion types. The estimation of divergence time indicated that the differentiation of Daphniphyllaceae and Altingiaceae at around 29.86 Mya might be due to the dramatic uplift of Tibetan Plateau during the Oligocene. About 75% of codon changes in organelles were found to be hydrophilic to hydrophobic amino acids. The RNA editing in protein-coding transcripts is the result of amino acid changes to increase their hydrophobicity and conservation in alleles, which may contribute to the formation of functional 3D structures in proteins. This study would enrich genomic resources and provide valuable insights into the structural dynamics and molecular biology of Daphniphyllaceae species.

SARS-CoV-2 excretion and genetic evolution in nasopharyngeal and stool samples from primary immunodeficiency and immunocompetent pediatric patients

BackgroundPrimary Immunodeficiency disorders (PID) can increase the risk of severe COVID-19 and prolonged infection. This study investigates the duration of SARS-CoV-2 excretion and the genetic evolution of the virus in pediatric PID patients as compared to immunocompetent (IC) patients.Materials and methodsA total of 40 nasopharyngeal and 24 stool samples were obtained from five PID and ten IC children. RNA detection was performed using RT-qPCR, and whole-genome sequencing was conducted with the NexSeq 1000 platform. Data analysis used the nextflow/viralrecon pipeline. Hotspot amino acid frequencies were investigated using GraphPad Prism v10. Phylodynamic analysis was conducted with BEAST software.ResultsIn IC children, the viral excretion period lasted up to 14 days in nasopharyngeal swabs, with an average duration of 7 days, and ranged from 7 to 14 days in stool samples. In PID patients, the viral RNA was detected in nasopharyngeal for periods between 7 and 28 days, with an average duration of 15 days, and up to 28 days in stool samples. Two SARS-CoV-2 variants were detected in PID patients: Delta (AY.122) and Omicron (BA.1.1). Patients with antibody and combined deficiencies, exhibited the most prolonged shedding periods in both nasopharyngeal and stool samples and one patient presented complications and fatal outcome. Specific Hotspot amino acid changes were detected in PID: A2821V and R550H (ORF1ab).ConclusionOur findings underscore the prolonged excretion of SARS-CoV-2 RNA in patients with antibody and combined deficiencies. Thus, specialized care is essential for effectively managing PID patients.

Characterization, Quantification, and Molecular Identification of Co-Infection of Canine Parvovirus (CPV-2) Variants in Dogs Affected by Gastroenteritis in Ecuador During 2022-2023.

Canine parvovirus (CPV-2) is a highly contagious virus in canines, and it is mostly spread by touching infected feces. Dogs of all ages can catch it, but puppies are more likely to suffer from it. Severe signs include vomiting, diarrhea with blood, feeling tired, and not drinking enough water. There are three different types of the original CPV-2 that have been found so far, which are CPV-2a, 2b, and 2c. The genome of CPV-2 is about 5.2 kb long and has two open reading frames (ORFs), namely the VP region and the NS region. Based on changes in amino acids at position 426, the VP2 protein distinguishes the gene apart in the VP region. Using a molecular method, this study contemplated the presence of CPV-2 and its variants in dogs that had gastroenteritis, as well as other infections. There were 511 samples tested, and 401 (78.47%) of them were positive for CPV-2. Of these, 144 (25.91%) were positive for the original genotype, 258 (64.34%) for genotype 2a, 343 (85.54%) for genotype 2b, and 167 (41.65%) for genotype 2c. Using the multiplex qPCR for genotyping, CPV-2a and CPV-2b were determined as the most frequent co-infections (16.45%). The three genotypes (2a, 2b, and 2c) were found in the samples examined based on the amino acids at position 426 of the VP2 protein, as demonstrated by the VP2 gene sequencing. Furthermore, it was discovered that in certain samples, a genetic modification at position 297 was connected to the virus's pathogenicity.

Exploring metabolic reprogramming in esophageal cancer: the role of key enzymes in glucose, amino acid, and nucleotide pathways and targeted therapies.

Esophageal cancer (EC) is one of the most common malignancies worldwide with the character of poor prognosis and high mortality. Despite significant advancements have been achieved in elucidating the molecular mechanisms of EC, for example, in the discovery of new biomarkers and metabolic pathways, effective treatment options for patients with advanced EC are still limited. Metabolic heterogeneity in EC is a critical factor contributing to poor clinical outcomes. This heterogeneity arises from the complex interplay between the tumor microenvironment and genetic factors of tumor cells, which drives significant metabolic alterations in EC, a process known as metabolic reprogramming. Understanding the mechanisms of metabolic reprogramming is essential for developing new antitumor therapies and improving treatment outcomes. Targeting the distinct metabolic alterations in EC could enable more precise and effective therapies. In this review, we explore the complex metabolic changes in glucose, amino acid, and nucleotide metabolism during the progression of EC, and how these changes drive unique nutritional demands in cancer cells. We also evaluate potential therapies targeting key metabolic enzymes and their clinical applicability. Our work will contribute to enhancing knowledge of metabolic reprogramming in EC and provide new insights and approaches for the clinical treatment of EC.

Characterizing phenotype variants of Cercosporidium personatum, causal agent of peanut late leaf spot disease, their morphology, genetics and metabolites

Cercosporidium personatum (CP) causes peanut late leaf spot (LLS) disease with 70% yield losses unless controlled by fungicides. CP grows slowly in culture, exhibiting variable phenotypes. To explain those variations, we analyzed the morphology, genomes, transcriptomes and chemical composition of three morphotypes, herein called RED, TAN, and BROWN. We characterized, for the first time in CP, anthraquinone (AQ) precursors of dothistromin (DOT), including averantin, averufin, norsolorinic acid, versicolorin B, versicolorin A, nidurufin and averufanin. BROWN had the highest AQ and melanin (15 mg/g DW) contents. RED had the highest ergosterol (855 µM FW) and chitin (beta-glucans, 4% DW) contents. RED and TAN had higher resistance to xenobiotics (p ≤ 1.0E-3), including chlorothalonil, tebuconazole and caffeine, compared to CP NRRL 64,463. In RED, TAN, and BROWN, rates of single nucleotide polymorphisms (SNP) (1.4–1.7 nt/kb) and amino acid changes (3k-4k) were higher than in NRRL 64,463. Differential gene expression (p ≤ 1.0E-5) was observed in 47 pathogenicity/virulence genes, 41 carbohydrate-active enzymes (CAZymes), and 23 pigment/mycotoxin biosynthesis genes. We describe the MAT1 locus, and a method to evaluate CP-xenobiotic resistance in 5 days. Chemical profiles indicate each CP morphotype could trigger different immune response in plants, probably hindering development of durable LLS resistance.

Improving functional protein generation via foundation model-derived latent space likelihood optimization.

A variety of deep generative models have been adopted to perform de novo functional protein generation. Compared to 3D protein design, sequence-based generation methods, which aim to generate amino acid sequences with desired functions, remain a major approach for functional protein generation due to the abundance and quality of protein sequence data, as well as the relatively low modeling complexity for training. Although these models are typically trained to match protein sequences from the training data, exact matching of every amino acid is not always essential. Certain amino acid changes (e.g., mismatches, insertions, and deletions) may not necessarily lead to functional changes. This suggests that maximizing the training data likelihood beyond the amino acid sequence space could yield better generative models. Pre-trained protein large language models (PLMs) like ESM2 can encode protein sequences into a latent space, potentially serving as functional validators. We propose training functional protein sequence generative models by simultaneously optimizing the likelihood of training data in both the amino acid sequence space and the latent space derived from a PLM. This training scheme can also be viewed as a knowledge distillation approach that dynamically re-weights samples during training. We applied our method to train GPT- like models (i.e., autoregressive transformers) for antimicrobial peptide (AMP) and malate dehydrogenase (MDH) generation tasks. Computational experiments confirmed that our method outperformed various deep generative models (e.g., generative adversarial net, variational autoencoder, and GPT model without the proposed training strategy) on these tasks, demonstrating the effectiveness of our multi-likelihood optimization strategy.

Integrated proteomic and metabolomic analysis reveals the potential therapeutic mechanism of Quanduzhong capsule in rats with spontaneous hypertension and knee osteoarthritis

Quanduzhong capsule (QDZ), derived from Eucommia ulmoides Oliv., has been traditionally used in Chinese medicine for its beneficial effects on musculoskeletal health. Its clinical application has extended to conditions such as spontaneous hypertension combined with knee osteoarthritis (SKOA). However, the specific mechanisms by which QDZ alleviates symptoms and improves outcomes in this complex condition remain to be fully elucidated. This study aims to evaluate the therapeutic potential of QDZ in treating SKOA. By performing serum proteomics and metabolomics, we seek to explore the related biological pathways and elucidate the mechanisms underlying QDZ's effects on SKOA. Serum samples from control, spontaneous hypertension (SHR), SKOA, and SKOA treated with QDZ groups were analyzed using data-independent acquisition-based proteomics to identify differentially expressed proteins. Serum levels of angiotensin II, norepinephrine, endothelin-1, classical pro-inflammatory factors such as macrophage colony-stimulating factor, tumor necrosis factor-alpha, and interleukin-1 beta were measured. Additionally, serum metabolomics was performed to examine the changes in metabolite profiles. Correlation analysis was conducted to link changed proteins and metabolites with key pathways affected by QDZ. Proteomics analysis revealed significant alterations in serum protein expression between control, SHR, and SKOA groups, with changes in pathways related to immune regulation and vascular function. KEGG enrichment analysis highlighted pathways such as endocytosis, synaptic vesicle cycling, and immune responses were enriched in SKOA group compared with control group. QDZ treatment significantly modulated above pathways and reduced inflammatory and cardiovascular markers which were upregulated in SKOA group. Metabolomics analysis showed that QDZ reversed SKOA-induced changes in amino acid and organic acid metabolism, affecting pathways including valine, leucine, and isoleucine metabolism, as well as the TCA cycle. Correlation analysis revealed significant relationships between key proteins and metabolites, underscoring the integrated role of immune and metabolic pathways in QDZ's effects. Our results indicate QDZ has a significant therapeutic potential for SKOA by modulating both protein and metabolite profiles associated with inflammation, vascular dysfunction, and metabolic imbalance. Our findings provide insights into the mechanisms through which QDZ exerts its effects and support its use as a promising treatment for SKOA. This study highlights the impact of QDZ on proteomic and metabolomic alterations, offering a basis for its broader application in treating SKOA.

Longitudinal analysis for predicting amino acid changes in HIV-1 using association rule mining

Longitudinal analysis for predicting amino acid changes in HIV-1 using association rule mining

Learning the fitness dynamics of pathogens from phylogenies

The dynamics of the genetic diversity of pathogens, including the emergence of lineages with increased fitness, is a foundational concept of disease ecology with key public-health implications. However, the identification of such lineages and estimation of associated fitness remain challenging, and is rarely done outside densely sampled systems1,2. Here we present phylowave, a scalable approach that summarizes changes in population composition in phylogenetic trees, enabling the automatic detection of lineages based on shared fitness and evolutionary relationships. We use our approach on a broad set of viruses and bacteria (SARS-CoV-2, influenza A subtype H3N2, Bordetella pertussis and Mycobacterium tuberculosis), which include both well-studied and understudied threats to human health. We show that phylowave recovers the main known circulating lineages for each pathogen and that it can detect specific amino acid changes linked to fitness changes. Furthermore, phylowave identifies previously undetected lineages with increased fitness, including three co-circulating B. pertussis lineages. Inference using phylowave is robust to uneven and limited observations. This widely applicable approach provides an avenue to monitor evolution in real time to support public-health action and explore fundamental drivers of pathogen fitness.

Serum NMR metabolomics in distinct subtypes of hematologic malignancies.

Hematologic malignancies encompass a diverse array of subtypes, contributing to substantial heterogeneity that poses challenges in predicting clinical outcomes. Leveraging the capabilities of nuclear magnetic resonance holds substantial promise in the detection of serum biomarkers and individual metabolic alterations in patients. This study involved the analysis of the sera from patients with acute myeloid leukemia, chronic lymphocytic leukemia, and non-Hodgkin lymphoma to investigate the affected metabolites and their associated pathways. The quantitative one-dimensional (1D) 1H nuclear magnetic resonance method was employed to identify alterations. Metabolite annotations were validated using two-dimensional (2D) analyses. Discriminating chemometric models and receiver operating characteristic curves were created using the MetaboAnalyst platform. The findings revealed significant alterations in the serum levels of amino acid catabolism products, citrate cycle intermediates, and phospholipids. The acute myeloid leukemia group showed differences in glucogenic amino acids related to the glycolysis pathway, whereas the chronic lymphocytic leukemia and non-Hodgkin lymphoma groups displayed variances in fumarate and acetate levels linked to the citrate cycle pathway. In the leukemia groups, higher levels of products from the protein degradation pathway were observed. The biomarker panels for each malignancy group exhibited outstanding discrimination from controls. Healthy individuals differed distinctly from patients, indicating commonly observed metabolic adaptation patterns among frequent hematologic malignancies. The small cohort study using nuclear magnetic resonance metabolomics in various hematologic malignancy subtypes revealed significant changes in serum amino acid and protein degradation end-product levels, suggesting prolonged leukocyte lifespan and increased energy demand.